The development of overweight/obesity, metabolic disorders, and the nature of their interrelationships over the lifespan, from early childhood throughout adulthood, is a problem with immense public health implications. Visceral obesity, through its metabolic association with vascular inflammation, hormonal disturbances, and insulin resistance, plays a unique role in the etiology of many chronic diseases. Recent studies have demonstrated potential mechanistic links between visceral fat accumulation and increased deposition of fat in the liver. Increased fat accumulation in the liver may lead to insulin resistance, dyslipidemia, and risk for CVD and T2DM. However, little is currently known about the natural progression of liver fat accumulation in normal healthy individuals. This proposed research will use both new and existing data from the Fels Longitudinal Study, a unique database that began in 1929. The Fels Longitudinal Study is the world's longest continuous serial study of growth, body composition and risk factors for chronic disease in randomly ascertained individuals. A major focus of this continuation proposal is the comprehensive assessment of the role of adipose tissue in cardiometabolic disease risk. Liver fat content and abdominal adipose tissue in several depots will be quantified by magnetic resonance imaging (MRI) in order to examine the interrelationships among liver fat, visceral and subcutaneous abdominal adiposity, and total body adiposity with respect to risk for cardiometabolic diseases. These data will be combined with existing data to test a variety of hypotheses by conducting both serial and cross-sectional analyses. There are four specific aims to the proposed continuation: 1) Elucidate the determinants of liver fat and abdominal adipose tissue (visceral, superficial and deep subcutaneous) accrual in Fels Longitudinal Study participants;2) Elucidate associations and potential mechanistic pathways among different adipose tissue depots including the liver, abdomen (visceral, superficial and deep subcutaneous) and total body;3) Elucidate relationships among different adipose tissue depots (including the liver, abdomen, and total body) and cardiometabolic risk;and 4) Elucidate relationships among patterns of change in body composition, traditional CVD and T2DM risk factors, systemic inflammatory factors, and adipocytokines during childhood and adulthood using long-term serial data. The data collected under this competitive renewal proposal will provide a better and more complete understanding of the physiological relationships among different adipose tissue depots and risk for cardiometabolic diseases such as non- alcoholic fatty liver disease, CVD, and T2DM. PUBLIC HEALTH RELEVANCE: The development of overweight/obesity is a problem in the United States with immense public health implications. This proposed research uses data from the Fels Longitudinal Study, a unique database that began in 1929, to examine the inter-relationships between obesity, liver fat accrual and chronic disease risk.